Effect of Fluticasone Propionate Nasal Spray on Bioavailability of Intranasal Hydromorphone Hydrochloride in Patients With Allergic Rhinitis

George A. Davis, Pharm.D.; Anita C. Rudy, Ph.D.; Sanford M. Archer, M.D.; Daniel P. Wermeling, Pharm.D.; Patrick J. McNamara, Ph.D.

Disclosures

Pharmacotherapy. 2004;24(1) 

In This Article

Abstract and Introduction

Study Objective: To investigate the effect of the nasal corticosteroid fluticasone propionate on the bioavailability and pharmacokinetics of single-dose intranasal hydromorphone hydrochloride in patients with allergic rhinitis.
Design: Randomized, three-way, crossover pharmacokinetic study.
Setting: University clinical research unit.
Patients: Twelve patients with allergic rhinitis.
Intervention: Hydromorphone hydrochloride 2.0 mg was administered by intravenous infusion (treatment A), intranasal spray without allergic rhinitis treatment (treatment B), and intranasal spray after 6 days of fluticasone propionate (treatment C). Blood samples were collected serially from 0–16 hours.
Measurements and Main Results: Pharmacokinetic parameters were determined by noncompartmental methods. An analysis of variance (ANOVA) model was used for statistical analysis. Mean (% coefficient of variation) absolute bioavailability of intranasal hydromorphone was 51.9% (28.2) and 46.9% (30.3) in patients with allergic rhinitis with and without treatment with fluticasone propionate, respectively. Mean maximum concentration (Cmax) values were 3.02 and 3.56 ng/ml, respectively. No statistical differences in Cmax and area under the concentration versus time curve were detected between intranasal treatments. Bioavailability values for both intranasal treatments were lower than those in healthy volunteers (57%). Median time to Cmax (Tmax) values were significantly different (p=0.02) for treatments B and C (15 and 30 min, respectively) using rank-transformed Tmax for ANOVA. Adverse effects were consistent with known effects of hydromorphone administered by other routes, with the exception of bad taste after intranasal administration.
Conclusion: Hydromorphone was rapidly absorbed after nasal administration, with maximum concentrations occurring for most subjects within 30 minutes. Allergic rhinitis may affect pain management strategies for intranasal hydromorphone, with a delay in onset of action for patients treated with fluticasone propionate.

Methods to improve routes of delivery of opioid analgesics, including the intranasal route, are receiving growing interest.[1] Most patients with moderate-to-severe pain from cancer can be managed with oral opioids, but 33–70% require alternative routes of administration.[2–4] For ambulatory postoperative patients, oral opioids are the mainstay of pain control, but other routes are recommended for treatment of acute pain.[5] Nasal administration may have advantages over more invasive routes, including ease of administration, rapid onset, and patient control. Several opioids have been studied for intranasal administration, including alfentanil,[6] fentanyl,[7] sufentanil,[8] oxycodone,[9] buprenorphine,[10] butorphanol,[11] methadone,[12] and, most recently, hydromorphone.[13,14]

Hydromorphone, a µ-selective opioid agonist 5–8 times more potent than morphine, is effective in managing postoperative and moderate-to-severe chronic pain.[15–17] Similar to morphine, orally administered hydromorphone undergoes extensive first-pass effect resulting in a low and variable systemic bioavailability ranging from 10–65%.[18–21] Intranasal administration has been investigated because it bypasses gut metabolism and first-pass effect. A study of hydromorphone pharmacokinetics in healthy volunteers reported mean bioavailabilities of 52% and 57% after single intranasal doses of 1.0 and 2.0 mg, respectively.[14] In patients with nonallergic rhinitis, bioavailabilities were 54.4% and 59.8%, respectively, with and without rhinitis treatment (oral pseudoephedrine hydrochloride or intranasal oxymetazoline hydrochloride) (Davis et al, unpublished data, 2001). In both studies, intranasal hydromorphone was well tolerated, with bad taste being the most common adverse event.

Rhinitis (inflammation of the nasal mucosa) is classified by etiology as allergic or nonallergic. Allergic rhinitis is the most prevalent, affecting 20–40 million people in the United States annually.[22,23] Rhinitis is a hypersensitivity reaction manifested by increased cholinergic and sensory nerve activity in the nasal mucosa, resulting in one or more of the following symptoms: nasal itching, rhinorrhea, nasal congestion, and sneezing.[23] Parasympathetic nerve stimulation dilates arterioles, which causes increased permeability and congestion of the nasal mucosa and promotes nasal airway glands to increase secretion. Sensory nerve stimulation leads to perception of nasal itch and congestion that causes sneezing. The early inflammatory response of allergic rhinitis is mediated primarily by immunoglobulin E causing release of inflammatory mediators (e.g., histamine, leukotrienes, prostaglandins).[24–26] Late-phase response is characterized by T lymphocyte activation, production of TH2-type cytokines, and tissue eosinophilia.[25] Intranasal corticosteroids are the most effective agents for managing allergic rhinitis.[26–29] Corticosteroids potently inhibit T lymphocyte responses, and in clinical studies in subjects with allergic rhinitis, they were extremely effective in blocking both early- and late-phase allergic reactions.[27]

Because of the highly vascular nature of nasal tissues, inflammation from rhinitis results in increased nasal blood flow and permeability of the nasal mucosa.[30,31] It follows that inflammation and treatment with a nasally inhaled corticosteroid could alter the extent and rate of nasal absorption of other drugs. The objectives of our study were to assess the bioavailability and tolerance of a single dose of intranasal hydromorphone, and the effect of nasal corticosteroid fluticasone propionate on the rate and extent of absorption of intranasal hydromorphone in patients with allergic rhinitis.

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